The present invention relates to new substituted pyridine or piperidine compounds and to their use as facilitators of memory and cognition and as antalgic agents.
Ageing of the population due to increased life expectancy has brought with it a major increase in cognitive disorders associated with normal cerebral ageing and with pathological cerebral ageing occurring in the course of neurodegenerative diseases such as, for example, Alzheimer""s disease.
The majority of substances used today in treating cognitive disorders associated with ageing act by facilitating the central cholinergic systemsxe2x80x94either directly, as in the case of acetylcholinesterase inhibitors (tacrine donepezil) and cholinergic agonists (nefiracetam), or indirectly, as in the case of nootropic agents (piracetam, pramiracetam) and cerebral vasodilators (vinpocetine).
Besides their cognitive properties, substances acting directly on the central cholinergic systems often have antalgic properties but also have hypothermic properties, which can be undesirable.
It has been therefore been especially valuable to synthesise new compounds that are capable of opposing the cognitive disorders associated with ageing and/or of improving cognitive processes and that can possess antalgic properties without having hypothermic activity.
The literature discloses substituted piperidine compounds which are described as products of synthesis and/or of alkaloids (J. Chem. Soc., Perkin Trans. 1, 1991, (3), pp. 611-616; Heterocycles, 1985, 23 (4), pp. 831-834; Can. J. Chem., 1996, 74 (12), pp. 2444-2453).
Substituted pyridine compounds have also been described with reference to their synthesis (J. Chem. Soc., Dalton Trans., 1998, (6), pp. 917-922) or their interactions in metal complexes (J. Chem. Soc., Chem. Commun., 1987, (19), pp. 1457-1459; J. Am. Chem. Soc., 1985, 107 (4), pp. 917-925).
The compounds of the present invention are new and have properties that, from a pharmacological point of view, are especially valuable.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
♦ A represents a pyridine, pyridinium or piperidine group,
♦ R2 represents a hydrogen atom and R3 represents a hydroxy group,
or R2 and R3 together form an oxo group,
♦ R4 represents an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group or an unsubstituted or substituted heteroaryl group,
♦ R1 represents a hydrogen atom,
or R1 and R4, together with the two carbon atoms carrying them, form a ring containing 6 carbon atoms,
or R1 and R2 form an additional bond and, in that case, R3 represents a 5- or 6-membered heterocycle that contains a nitrogen atom by which it is bound and that may contain another hetero atom selected from sulphur, oxygen and nitrogen,
♦ R5 represents:
a 5- or 6-membered heterocycle that contains a nitrogen atom by which it is bonded to the ring A and that may contain another hetero atom selected from sulphur, oxygen and nitrogen,
a group of formula (II): 
xe2x80x83wherein Rxe2x80x21, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 may have the same meanings as R1, R2, R3 and R4, respectively,
or a hydrogen atom and, in that case, R4 cannot represent an unsubstituted phenyl group, an unsubstituted naphthyl group or an heteroaryl group,
♦ R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, the group R6 being present or absent depending on the nature of the ring A,
heteroaryl being understood to mean any aromatic, mono- or bi-cyclic, 5- to 10-membered group containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the expressions xe2x80x9cphenylxe2x80x9d, xe2x80x9cnaphthylxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d being understood to mean that the groups concerned may be substituted by one or more groups, which may be the same or different, selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, mercapto, linear or branched (C1-C6)-alkylthio, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched, linear or branched (C1-C6)polyhaloalkyl and hydroxy and halogen atoms,
it being understood that:
when R2 and R3 together form an oxo group and simultaneously R5 represents a hydrogen atom and R6 represents a hydrogen atom or does not exist, then R4 is other than a phenyl group substituted by one group selected from hydroxy, alkoxy, CF3 and halogen (except for bromine when A represents a piperidine group), or by several groups selected from hydroxy and alkoxy,
when R2 represents a hydrogen atom and R3 represents a hydroxy group and simultaneously R5 represents a hydrogen atom and R6 represents a hydrogen atom or does not exist, then R4 is other than a phenyl group substituted by one group selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl and chlorine, or by several groups selected from hydroxy and alkoxy,
the compound of formula (I) may not represent 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)ethanol nor 2-(2-pyridinyl)cyclohexanone,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methane-sulphonic acid, camphoric acid, oxalic acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are compounds of formula (I) wherein the group 
represents a pyridinyl group, an N-methylpyridinium group, a piperidinyl group or an N-methylpiperidinyl group.
Preferred substituents R4 are a phenyl group or substituted phenyl group, especially substituted by a halogen atom, preferably a bromine atom.
Advantageously, the invention relates to compounds of formula (I) wherein R5 represents a hydrogen atom or a group of formula (II).
Preferred groups R2 and R3 are those wherein R2 and R3 together form an oxo group or R2 represents a hydrogen atom and R3 represents a hydroxy group.
Even more advantageously, the invention relates to the compounds of formula (I) which are:
1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,
(R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,
(S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,
1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,
(S,S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,
(R,R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,
1-methyl-2-[2-oxo-2-(4-bromophenyl)ethyl]pyridinium iodide.
The enantiomers and diastereoisomers, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (III): 
wherein X represents a hydrogen or fluorine atom, which is alkylated by means of an agent such as, for example, alkyl para-toluenesulphonate or alkyl trifluoromethanesulphonate to yield the compound of formula (IV): 
wherein X is as defined hereinbefore, Rxe2x80x26 represents a linear or branched (C1-C6)alkyl group and Yxe2x88x92 represents a para-toluenesulphonate or trifluoromethanesulphonate group for example,
which is reacted with one or two compounds, which may be the same or different, of formula (V) 
xe2x80x83wherein Ra and Rb, together with the nitrogen atom carrying them, form a 5- or 6-membered heterocycle which may contain, in addition to the nitrogen atom, another hetero atom selected from sulphur, oxygen and nitrogen, and Rc represents a hydrogen atom or a group of formula (VI): 
xe2x80x83wherein R4 and R1 are as defined hereinbefore,
it being understood that at least one of the compounds of formula (V) contains a group of formula (VI),
to yield the compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1, R4, Ra, Rb, Rxe2x80x26 and Yxe2x88x92 are as defined hereinbefore and Xxe2x80x2 represents a hydrogen atom, a group xe2x80x94NRxe2x80x2aRxe2x80x2b (wherein Rxe2x80x2a and Rxe2x80x2b may have any of the meanings of Ra and Rb, respectively) or a group of formula (VII) 
xe2x80x83wherein Rxe2x80x2a, Rxe2x80x2b, Rxe2x80x21 and Rxe2x80x24 may have any of the meanings of Ra, Rb, R1 and R4, respectively,
which compound of formula (I/a) may be subjected to halohydric acid such as HCl, HBr or HI, or to the action of ammonium salts such as NH4+PF6xe2x88x92 to yield a compound of formula (I/axe2x80x2): 
xe2x80x83wherein R1, R4, Ra, Rb, Rxe2x80x26 and Xxe2x80x2 are as defined hereinbefore and Yxe2x80x2xe2x88x92 represents anion or a PF6xe2x88x92 group,
which compound of formula (I/axe2x80x2) may be hydrolysed using a concentrated hydrochloric acid solution to yield the compound of formula (I/b), a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R4, Rxe2x80x26 and Yxe2x80x2xe2x88x92 are as defined hereinbefore and Xxe2x80x3 represents a hydrogen atom, a group xe2x80x94NRxe2x80x2aRxe2x80x2b as defined hereinbefore or a group of formula (VIII): 
xe2x80x83wherein Rxe2x80x21, and Rxe2x80x24 may have any of the meanings of R1 and R4, respectively, the compounds of formula (I/a), (I/axe2x80x2) and (I/b) constituting the compound of formula (I/c) a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R4 and Rxe2x80x26xe2x88x92 are as defined hereinbefore, Yxe2x80x3xe2x88x92 represents a group Yxe2x88x92 or Yxe2x80x2xe2x88x92 as defined hereinbefore, R2a and R3a together form an oxo group, or R2a and R1 form an additional bond and, in that case, R3a represents a group NRxe2x80x2aRxe2x80x2b as defined hereinbefore, and Xxe2x80x2xe2x80x3 represents a hydrogen atom, a group NRxe2x80x2aRxe2x80x2b or a group of formula (IX): 
wherein Rxe2x80x21, Rxe2x80x22a, Rxe2x80x23a and Rxe2x80x24 may have any of the meanings of R1, R2a, R3a and R4, respectively,
which is converted into a corresponding iodinated salt by the action of NaI to yield the compound of formula (I/d), a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2a, R3a, R4, Rxe2x80x26 and Xxe2x80x2xe2x80x3 are as defined hereinbefore,
which is
either subjected to catalytic hydrogenation, for example over platinum oxide, to yield the compound of formula (I/e), a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2a, R3a, R4, Xxe2x80x2xe2x80x3 and Rxe2x80x26 are as defined hereinbefore,
or subjected to the action of a pyridinium salt to yield the compound of formula (I/f), a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2a, R3a, R4 and Xxe2x80x2xe2x80x3 are as defined hereinbefore,
which may be hydrogenated by catalytic hydrogenation to yield the compound of formula (I/g), a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2a, R3a, R4 and Xxe2x80x2xe2x80x3 are as defined hereinbefore,
it being possible for the compounds of formulae (I/b) and (I/c) to (I/g) wherein R2a and R3a together form an oxo group to be subjected to the action of a reducing agent such as, for example, NaBH4 to yield the compound of formula (I/h), a particular case of the compounds of formula (I): 
xe2x80x83wherein A, R1, R4 and R6 are as defined hereinbefore and Xxe2x80x2xe2x80x3 represents a hydrogen atom, a group NRxe2x80x2aRxe2x80x2b as defined hereinbefore or a group of formula (X): 
xe2x80x83wherein Rxe2x80x21, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 are as defined hereinbefore,
which compound of formula (I/h) can be obtained as pure enantiomers from compounds of formula (I/b) and (I/c) to (I/g) wherein R2a and R3a together form an oxo group using an enantioselective reduction catalyst such as (R,R)-(xe2x88x92) or (S,S)-(+)-N,Nxe2x80x2-bis(3,5-di-tert-butylsalicylidene-1,2-cyclohexanediaminomanganese (III) chloride,
the compounds of formulae (I/a) to (I/h) constituting the totality of the compounds of the invention, which may be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and are separated, where appropriate, into their isomers according to a conventional separation technique.
In addition to the fact that the compounds of the present invention are new, they exhibit antalgic properties and properties facilitating cognitive processes, rendering them of use in the treatment of pain and of cognitive deficiencies associated with cerebral ageing and with neurodegenerative diseases, such as Alzheimer""s disease, Parkinson""s disease, Pick""s disease, Korsakoff""s disease and frontal lobe and subcortical dementias.
The invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) and nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The dosage used can be adapted to the nature and the severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 0.01 mg to 1 g per day in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
The following Preparations yield compounds of the invention or synthesis intermediates that are useful in the preparation of compounds of the invention.
Preparation 1: 2-Fluoro-1-methylpyridinium 4-methylbenzenesulphonate
10 mmol of 2-fluoropyridine and 10 mmol of methyl 4-methylbenzenesulphonate are mixed in a 50 ml round-bottomed flask and stirred for 6 hours at 70xc2x0 C. under a nitrogen atmosphere. The salt obtained in the form of a white solid is used without additional purification in the following step.
Preparation 2: 1-(1-Phenylvinyl)pyrrolidine
100 g of molecular sieve are heated at 500xc2x0 C. for 8 hours and then added to a mixture of 20 mmol of acetophenone and 22 mmol of pyrrolidine in 200 ml of anhydrous ether. The reaction mixture is stirred at ambient temperature until, in the infra-red, no more free ketone (Cxe2x95x90O 1689 cmxe2x88x921) is detected in the supernatant and the absorption for the enamine (Cxe2x95x90Cxe2x80x94N 1600 cmxe2x88x921) is at a maximum. The mixture is then filtered and the molecular sieve is washed with ether. The solvent is evaporated off under reduced pressure and the crude residue is purified by distillation under reduced pressure.
Boiling point: 110xc2x0 C./2 mm Hg
Preparations 3 to 11 are obtained by proceeding as in Preparation 2.
Preparation 3: 4-(1-Phenylvinyl)morpholine
Boiling point: 125xc2x0 C./2 mm Hg
Preparation 4: 1-[1-(4-Methylphenyl)vinyl]pyrrolidine
Boiling point: 135xc2x0 C./10 mm Hg
Preparation 5: 1-[1-(4-Methoxyphenyl)vinyl]pyrrolidine
Boiling point: 160xc2x0 C./0.4 mm Hg
Preparation 6: 1-[1-(4-Chlorophenyl)vinyl]pyrrolidine
Boiling point: 125xc2x0 C./10 mm Hg
Preparation 7: 1-[1-(4-Bromophenyl)vinyl]pyrrolidine
Boiling point: 160xc2x0 C./0.3 mm Hg
Preparation 8: 1-[1-(4-Fluorophenyl)vinyl]pyrrolidine
Boiling point: 140xc2x0 C./0.3 mm Hg
Preparation 9: 1-[1-(2-Bromophenyl)vinyl]pyrrolidine
Boiling point: 130xc2x0 C./0.3 mm Hg
Preparation 10: 1-[1-(3-Bromophenyl)vinyl]pyrrolidine
Boiling point: 165xc2x0 C./0.3 mm Hg
Preparation 11: 1-(1-Cyclohexen-1-yl)pyrrolidine
1 g of para-toluenesulphonic acid is added to a mixture of 20 mmol of cyclohexanone and 22 mmol of pyrrolidine in 200 ml of dry benzene. The reaction mixture is stirred at reflux until, in the infra-red, the ketone has disappeared, with the enamine concomitantly appearing. The solvent is then evaporated off and the crude residue is purified by distillation in vacuo.
Boiling point: 110xc2x0 C./15 mm Hg
Preparation 12: 1-(1-Cyclohexen-1-yl)morpholine
The procedure is as in Preparation 11, the benzene being replaced by toluene and the pyrrolidine by morpholine.
Boiling point: 140xc2x0 C./15 mm Hg
Preparation 13: 2,6-Difluoro-1-methylpyridinium trifluoromethanesulphonate
10 mmol of 2,6-difluoropyridine and 10 mmol of trifluoromethanesulphonic acid are mixed in a 50 ml round-bottomed flask and the mixture is stirred for 1 hour at ambient temperature under a nitrogen atmosphere. The white solid obtained is used directly in the following reaction without further purification.
Preparation 14: 1-{1-[4-(Dimethylamino)phenyl]vinyl}pyrrolidine
The procedure is as in Preparation 2.
Preparation 15: 1-[1-(2-Fluorophenyl)vinyl]pyrrolidine
The procedure is as in Preparation 2.
Preparation 16: 1-{1-[4-(Methylthio)phenyl]vinyl}pyrrolidine
The procedure is as in Preparation 2.
Preparation 17: 1-{1-[4-(Trifluoromethyl)phenyl]vinyl}pyrrolidine
The procedure is as in Preparation 2.
Preparation 18: 2-Fluoro-1-ethylpyridinium-4-methylbenzenesulfonate
Title product is obtained using the same procedure than in Preparation 1 replacing methyl-4-methylbenzenesulfonate by ethyl-4-methylbenzenesulfonate.